The mechanisms linking nutrient intake to altered bone formation are poorly understood. Although most research has focused on the calcium-PTH-Vitamin D axis, our laboratory has a longstanding interest defining the mechanisms utilized by enteric hormones to modulate bone turnover. During the conduct of our research, we observed that nutrients not only affect bone turnover by indirect mechanisms (e.g. by modulating release ofbone acfive hormones such as IGF-1, GLP-2, GIP or by modulating the activity of the innervation in bone) but also exert direct effects on bone marrow stem cells (BMSCs). Although it has been known for some time that nutrients can modulate osteoblastic and osteoclastic activity, direct nutrient effects on BMSCs have not been demonstrated. Preliminary data presented in this proposal support a role for direct, receptor-mediated nutrient effects on BMSC proliferation, specifically: (1) BMSC do not grow or differentiate in growth mediums with low amino acid concentrations;(2) BMSC express extracellular L-type amino acid sensors [the calcium sensing receptor (CasR) and the taste receptor (Tl R1/T1R3)];(3) aromafic amino acids increase intracellular calcium;(4) aromatic amino acids and glutamate activate the MAPK signaling pathway;(5) expression and funcfion of speciflc extracellular amino acid sensors vary in an age-dependent manner;and (6) aging C57BI6 mice fed a low protein diet lose bone and this loss is prevented by dietary supplementafion of aromafic amion acids. We hypothesize that direct nutrient effects on BMSCs play an important role in preserving bone mass. This proposal focuses on defining the contribution of direct nutrient effects on BMSCs to bone formation using interrelated in vivo and in vitro studies. Therefore, the specific aims of the proposal are: (1) To define the molecular mechanisms involved in direct amino acid induced BMSC/Osteoprogenitor cell activation in vitro;and (2) To define the effect of dietary nutrients (protein) on bone mass in vivo. Findings from the proposed experiments should help reveal and define the mechanistic links between nutrient ingesfion and bone formation and result in new targets for therapeutics, particularly those targeted to age-dependent alterations in bone formafion. This project also will explore the interactions between amino acid effects on BMSC with the fat and muscle derived hormones, lepfin and IGF-1 and the cytokine SDF-1 and thus provides a unique opportunity to examine nutrient effects on bone in a comprehensive manner.
Nutrition has long been known to be important for the maintenance of bone health although the pathophysiological mechanisms is not know. The proposed studies will for the first fime shed some light on how to maximize nutrient effects on bone mass.
|LÃ³pez, Melany; Bollag, Roni J; Yu, Jack C et al. (2016) Chemically Defined and Xeno-Free Cryopreservation of Human Adipose-Derived Stem Cells. PLoS One 11:e0152161|
|Howie, R Nicole; Durham, Emily L; Black, Laurel et al. (2016) Effects of In Utero Thyroxine Exposure on Murine Cranial Suture Growth. PLoS One 11:e0167805|
|Withrow, Joseph; Murphy, Cameron; Liu, Yutao et al. (2016) Extracellular vesicles in the pathogenesis of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 18:286|
|Durham, Emily L; Howie, R Nicole; Black, Laurel et al. (2016) Effects of thyroxine exposure on the Twist 1 +/- phenotype: A test of gene-environment interaction modeling for craniosynostosis. Birth Defects Res A Clin Mol Teratol 106:803-813|
|Bhatta, Anil; Sangani, Rajnikumar; Kolhe, Ravindra et al. (2016) Deregulation of arginase induces bone complications in high-fat/high-sucrose diet diabetic mouse model. Mol Cell Endocrinol 422:211-20|
|Hamrick, Mark W; McGee-Lawrence, Meghan E; Frechette, Danielle M (2016) Fatty Infiltration of Skeletal Muscle: Mechanisms and Comparisons with Bone Marrow Adiposity. Front Endocrinol (Lausanne) 7:69|
|Sangani, Rajnikumar; Periyasamy-Thandavan, Sudharsan; Pathania, Rajneesh et al. (2015) The crucial role of vitamin C and its transporter (SVCT2) in bone marrow stromal cell autophagy and apoptosis. Stem Cell Res 15:312-21|
|El Refaey, Mona; Watkins, Christopher P; Kennedy, Eileen J et al. (2015) Oxidation of the aromatic amino acids tryptophan and tyrosine disrupts their anabolic effects on bone marrow mesenchymal stem cells. Mol Cell Endocrinol 410:87-96|
|Herberg, Samuel; Aguilar-Perez, Alexandra; Howie, R Nicole et al. (2015) Mesenchymal stem cell expression of SDF-1Î² synergizes with BMP-2 to augment cell-mediated healing of critical-sized mouse calvarial defects. J Tissue Eng Regen Med :|
|Herberg, Samuel; Kondrikova, Galina; Hussein, Khaled A et al. (2015) Mesenchymal stem cell expression of stromal cell-derived factor-1Î² augments bone formation in a model of local regenerative therapy. J Orthop Res 33:174-84|
Showing the most recent 10 out of 33 publications